Phenothiazine tranquilizers undergo extensive biotransformation in the body. One of the metabolites, 7,8-dihydroxychlorpromazine, has been recently identified in patients receiving chlorpromazine, and shown to be pharmacologically active. In vitro, it inhibits Na plus K ions- ATPase and releases calcium from mitochondria. Preliminary studies in this laboratory indicate that 7,8-dihydroxychlorpromazine produces a positive inotropic and chronotropic effect in the isolated guinea pig heart. It fails to produce arrhythmias even at high concentrations and rather would appear to reverse ouabain-induced arrhythmias. Pharmacologic properties of chemically related phenothiazine metabolites will be studied in left atrial and Langendorff preparations of guinea pig hearts and in open-chest anesthetized dogs. In order to elucidate the molecular mechanims of these actions, effects of these agents on Na plus k ions-ATPase, and the partial reactions associated with this enzyme activity, will be studied using crude enzyme preparations obtained from guinea pig heart and partially purified enzyme preparations obtained from rat brain. Interactions of these agents with Beta-adrenergic agonists and antagonists will also be studied. It is expected that a potential cardiotonic agent with no arrhythmogenic properties or an antiarrhythmic agent with positive inotropic properties will be uncovered and that an insight into the mechanisms by which drugs alter cardiac functions may be obtained. Additionally, the molecular mechanisms for cardiac toxicity of phenothiazine tranquilizers may be elucidated.